2016 TAT: Guadecitabine (SGI-110), a novel partner in immunotherapy

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Summary

  • Guadecitabine(SGI-110) is a novel hypomethylatingdinucleotide of decitabine(DAC) and deoxyguanosinethat is resistant to degradation by cytidine deaminase and results in prolonged in vivo exposure to its active metabolite DAC. The differentiated pharmacokinetic profile offers the potential of improved biological and clinical activity and safety over currently available hypomethylatingagents (HMA).
  • We reported previously results from the Phase 1 dose-escalation study in AML and MDS1and the Phase 2 randomized dose-response study in r/r AML patients of SGI-110 given SC at 2 doses (60 and 90 mg/m2) in a 5-day regimen2or at 60 mg/m2in a 10-day regimen.
  • Rationale for guadecitabinecombination with immunomodulating agents
    • Tumor Associated Antigens (TAAs) including Cancer Testis Antigens (CTAs) e.g. NY-ESO-1 and MAGE-A are often silenced by hypermethylation
    • Guadecitabine demethylates and induces CTA re-expression rendering the tumor more immunogenic
    • Guadecitabine induces better tumor recognition by immune system (cytotoxic CD8+ T lymphocytes)
    • Clinical correlation between hypermethylationand poor survival reported in Melanoma and Liver Cancer
    • Anecdotal clinical data from patients treated with HMA and immunotherapy
  • Guadecitabineimmunomodulatory data
    • Preclinical In vitro Data:
      • Guadecitabine demethylates the promoters and induces the expression of CTAs MAGE-A3, NY-ESO-1 in cancer cell lines
      • Guadecitabine induces tumor recognition by cytotoxic T lymphocytes
    • Preclinical In vivo Data
      • Synergy when guadecitabineis combined with CTLA-4 antibody
    • Clinical Data
      • Guadecitabine achieves dose-dependent demethylation and induction of CTAs (NY-ESO-1; MAGE-A1 and A3) in AML and MDS patients

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2016 TAT: Guadecitabine (SGI-110), a novel partner in immunotherapy